The overarching goal of this proposed Lewy body dementia (LBD) center without walls (CWOW) is to understand synergistic interactions of amyloid-beta (A?) and alpha-synuclein (?-syn) and to determine how genetic risk factors, such as apolipoprotein E4, contribute to LBD pathogenesis. Using well-characterized postmortem brain tissue from the Mayo Clinic Brain Bank, CWOW investigators will probe genetics, transcriptomics, proteomics, lipidomics, structure, biochemistry, and function of A? and ?-syn species in LBD. The CWOW has an Administrative Core and a Neuropathology and Biochemistry Core, as well as four research projects. The Administrative Core will provide fiscal and scientific oversight, management, and reporting functions. The Neuropathology and Biochemistry Core will provide neuropathologically well- characterized LBD brain samples and quantitative endophenotypes to all projects. The research projects are led by highly qualified investigators who focus on complementary and fundamental aspects of LBD. Project 1 will explore genetic correlates of clinical and pathologic heterogeneity of LBD, as well as cell-specific transcript data from single nuclei sequencing to build network analyses, which will provide insights into underlying disease mechanisms. Project 2 will identify and validate proteins and low-abundant bioactive lipid species in LBD brains that may be important to the unique pathologic signature of LBD. Project 3 will use state-of-the?art cryo-EM techniques to characterize the native and molecular structures of ?-syn and A? filaments in LBD brain to generate novel insight into the etiology, toxicity and spreading of protein aggregates in this disease. Project 4 will isolate and characterize A? and ?-syn subspecies from postmortem brains and use cellular models to reveal mechanistic insight into toxic pathways contributing to disease pathogenesis. We envision that, at the conclusion of the funding period, we will have made significant progress towards understanding unique structural and molecular features of LBD and how genetics and interactions between A? and ?-syn contribute to the unique symptoms, progression, and underlying pathology of LBD.